The present invention relates to (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol and its use in medical therapy.
Hepatitis B virus (HBV) is a small DNA containing virus which infects humans. It is a member of the class of closely related viruses known as the hepadnaviruses, each member of which selectively infects either mammalian or avian hosts, such as the woodchuck and the duck. Recent insights into the mechanism of replication of the hepadnavirus genome indicate the importance of reverse transcription of an RNA intermediate, suggesting that the reverse transcriptase is a logical chemotherapeutic target. HBV is a viral pathogen of major worldwide importance. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world""s liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
U.S. Pat. No. 4,916,224 discloses dideoxycarbocyclic nucleosides and their use in the treatment of HIV. Wang et al. (Bioorganic Et Medicinal Chemistry Letters 8, pp. 1585-1588, 1998) disclose the synthesis of L-carbocyclic 2xe2x80x2,3xe2x80x2-didehydro-2xe2x80x2,3xe2x80x2-dideoxyadensosine and its use in HIV infections.
An aspect of the present invention relates to the use of (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol in the treatment of Hepatitis B infections.
The present invention features compounds of formula (I) 
also known as (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol and pharmaceutically acceptable salts thereof for the prophylaxis and treatment of Hepatitis B infections.
Physiologically acceptable salts of (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids. For therapeutic use, salts of (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid. However, salts of acids which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid, are within the scope of the present invention. A preferred salt of (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol is the succinate salt. (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol may be synthesized by the known 3-step sequence (see, e.g., Y. F. Shealy and J. D. Clayton, J. Amer. Chem. Soc. 1969, 91: 3075-3887 and references therein) involving the condensation of (1S,4R)-4-amino-2-cyclopentene-1-methanol or a salt thereof (4) with 5-amino-6-chloropyrimidine 
in refluxing n-butanol in the presence of an excess of a non-nucleophilic base, e.g. triethylamine. The resulting pyrimidine intermediate (5) may be converted to the 6-chloropurine intermediate (6) by triethylorthoformate in the presence of a catalytic amount of acid. Amination of (6) with ammonia may provide (I) in good yield and purity.
(1S,4R)-4-amino-2-cyclopentene-1-methanol may be synthesized in 3 steps from (+)-2-azabicyclo[2.2.1]hept-5-en-3-one, for example, as in Example 1.
In one aspect of the present invention there is provided (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol, or a pharmaceutically acceptable salt thereof for use in medical therapy, particularly for the treatment of hepatitis B virus infections.
The present invention features a method for the treatment of a hepatitis B virus infection in a host comprising administering to said host a therapeutically effective amount of (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol or a pharmaceutically acceptable salt thereof. Preferably the host is a human.
Another aspect of the present invention features the use of (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a hepatitis B virus infection.
(1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol, also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the chosen active ingredient.
The amounts required of the active ingredient will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician or veterinarian. In general however, for each of these utilities and indications, a suitable effective dose of a compound of formula (I) will be in the range of 0.01 to 100 mg per kilogram body weight of recipient per day, advantageously in the range of 1 to 70 mg per kilogram body weight per day, preferably in the range of 1 to 50 mg per kilogram body weight per day.
The desired dose is preferably presented as one, two, three or four or more subdoses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 25 to 2000 mg, preferably about 25, 50, 100, 150, 200, or 250 mg of active ingredient per unit dose form.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. A further aspect of the present invention features pharmaceutical compositions comprising (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
The compositions of the present invention may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing in to association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets of granules or tablets (such as a swallowable, dispersible or chewable tablet) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredient therein.
Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Compositions for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solution which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multidose sealed containers, for example, ampoules and vial, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
The active ingredient may also be presented in a composition comprising micrometer- or nanometer-size particles of active ingredient.
Preferred unit dosage compositions are those containing a daily dose or unit daily sub-dose (as herein above recited) or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the composition of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents or taste masking agents.
A further aspect of the invention relates to kits to be used in the treatment of patients suffering from viral infections. These kits include one or more oral dosage of a compound of formula (I) and may include one or more additional therapeutic agents. By way of illustration, a kit of the invention may include one or more tablets, capsules, caplets, gelcaps or liquid formulations containing a compound of formula (I) and one or more tablets, capsules, caplets, gelcaps or liquid formulations containing a compound of formula (I) in dosage amounts within the ranges described above. The kits may include as an insert printed dosing information for the co-administration of the agents.
The active ingredient may also be presented in a composition comprising micrometer- or nanometer-size particles of active ingredient.
(1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol may be administered with other therapeutic agents. Other therapeutic agents may include agents that are effective for the treatment of viral infections or associated conditions such as nucleoside reverse transcriptase inhibitors, for example, zidovudine or abacavir, 2xe2x80x2,3xe2x80x2-dideoxycytidine, 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine, 2xe2x80x2,3xe2x80x2-didehydrothymidine; (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(xe2x88x92)BHCG, SQ-34514]; oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine); acyclic nucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir); acyclic nucleoside phosphonates (e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC) or PMEA; protease inhibitors such as indinavir, ritonavir, nelfinavir, amprenavir, sanquinavir; oxathiolane nucleoside analogues such as lamivudine, cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), dioxolane G, L-FMAU; tat inhibitors such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335), 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1,4-benzodiazepin-2-amine (Ro24-7429); interferons such as a-interferon; renal exeretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, xcex1-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD4 and genetically engineered derivatives thereof; or non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG-587), loviride (xcex1-APA) and delavuridine (BHAP), and phosphonoformic acid, and 1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs such as (xe2x88x92)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and quinoxaline NNRTIs such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1 (2H)-quinoxalinecarboxylate (HBY1293). The therapeutic agents, including (1R,4S)-4-(6-amino-9H-purin-9-yl)-2-cyclopentene-1-methanol may be administered concurrently, sequentially, or as part of the same composition.